Type 2 diabetes mellitus is a chronic disease characterized by hyperglycemia caused by hepatic glucose production, a deficiency in insulin secretion, and/or peripheral insulin resistance. In recent years, considerable effort has been directed towards discovering ways of treating the disease. One relatively new approach is inhibition of the sodium glucose cotransporter (SLGT), which lowers blood glucose levels by removing glucose from the bloodstream.
Under normal conditions, plasma glucose is filtered in the kidney glomerulus and in healthy individuals is almost completely reabsorbed. Obermeier, M., et al., Drug Metabolism Disposition 38(3):405-414, 406 (2010). That reabsorption is mediated by two sodium-dependent glucose cotransporters: SGLT1 and SGLT2. SGLT1 is expressed in the gut, heart, and kidney, while SGLT2 is expressed primarily in the proximal tubule of the nephron. Id. Although compounds that inhibit both transporters have been described, research has largely focused on discovering selective SGLT2 inhibitors. This is due, in part, to the discovery that a defective SGLT1 transporter in the gut is responsible for some glucose and galactose malabsorption disorders, and the belief that inhibition of SGLT1 would therefore be attended by unacceptable adverse effects. Id. Thus, most SGLT inhibitors currently in clinical trials, including dapagliflozin, canagliflozin, and empagliflozin, are selective SGLT2 inhibitors.
Recent clinical trial results do suggest, however, that inhibition of SGLT1 can provide benefits that extend beyond those provided merely by the inhibition of glucose reabsorption. See, e.g., U.S. patent application publication no. US-2011-0218159. In particular, it is believed that inhibition of SGLT1 can increase glucagon-like peptide-1 (GLP-1) levels. See, e.g., Moriya, R., et al., Am J Physiol Endocrinol Metab 297: E1358-E1365 (2009). A number of well-known diabetes drugs, including sitagliptin, vildagliptin and saxagliptin, work by inhibiting dipeptidyl peptidase IV (DPP-4), which is the enzyme responsible for GLP-1 degradation.